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系統識別號 U0026-1102201522023000
論文名稱(中文) CCN1受小鼠頸動脈窄縮誘發之表現及其所引發之血管內膜新生的角色
論文名稱(英文) CCN1 induction and its role in the neointima formation-induced by carotid artery ligation in mice
校院名稱 成功大學
系所名稱(中) 細胞生物與解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 103
學期 1
出版年 104
研究生(中文) 陳正鑫
研究生(英文) Jheng-Sin Chen
學號 T96011012
學位類別 碩士
語文別 中文
論文頁數 64頁
口試委員 指導教授-莫凡毅
口試委員-江美治
口試委員-王仰高
中文關鍵字 動脈粥狀硬化  血管內膜新生  CCN1  頸動脈結紮  內皮細胞功能失調 
英文關鍵字 atherosclerosis  neointima formation  CCN1  carotid artery ligation  endothelial dysfunction 
學科別分類
中文摘要 動脈粥狀硬化(atherosclerosis)是一種慢性發炎疾病,血管內膜新生(neointima formation)為其一特徵,好發於血管分支以及彎曲處,歸因於擾流(disturbed flow)的產生造成該處血流剪應力(shear stress)較低或易變動。研究指出CCN1和動脈粥狀硬化有很大的關聯性,且在細胞實驗中,CCN1的表現在順向血流中較靜止培養時減少,所以CCN1是否會因為擾流所誘發及其造成血管內膜新生的角色是我們想知道的。在本篇研究中,我們使用頸動脈結紮動物模式(carotid artery ligation animal model)來引起擾流的產生促使血管內膜新生。首先我們使用Ccn1+/lacZ轉殖小鼠去觀察CCN1表現的情形,這種小鼠是將lacZ基因插入Ccn1啟動子(promotor)之後,所以當CCN1被表現時,β-半乳糖苷酶(β-galactosidase)會被製造出來,之後可以利用X-gal染色來觀察CCN1的表現,我們發現在術後3天CCN1就會被激發,隨著時間的增加,CCN1的量也上升,而有CCN1表現的區域也常伴隨血管內膜增生,且在術後3周表現量達到最大值。接著利用螢光染色標定發現內皮細胞(endothelial cell)、平滑肌細胞(smooth muscle cell)和巨噬細胞(macrophage)皆會表現CCN1。因CCN1常透過其受體整合素(integrin)α6β1引起發炎反應,我們使用會產生無法結合α6β1突變CCN1蛋白之Ccn1dm/dm轉殖鼠(DM)來測試CCN1在擾流所引發的血管內膜新生中的角色。在術後3周,DM小鼠血管內膜新生的情形比起野生型小鼠有顯著的減少,且在1周時,DM的內皮細胞功能和氧化壓力也有明顯的改善,顯示在有擾流產生的情況下,CCN1會透過和integrin α6β1結合造成內皮細胞功能失調(endothelial dysfunction)進而促進血管內膜新生。後續可發展藉抑制CCN1和其受器α6β1結合來防制動脈粥狀硬化。
英文摘要 Atherosclerosis, a chronic inflammatory disease characterized by neointima formation, occurs preferentially at areas of disturbed flow. Despite the close association between CCN1 and atherosclerotic lesion, the exact role of CCN1 in atherogenesis was not clear. To examine how CCN1 expression may be regulated by disturbed flow, we used carotid artery ligation animal model in Ccn1+/lacZ mice, in which a lacZ gene was inserted downstream of the Ccn1 promoter. We found that CCN1 was dynamically induced after ligation in endothelial cells, smooth muscle cells and macrophages. To assess the role of CCN1 in neointima formation, Ccn1dm/dm mice, in which Ccn1 locus was replaced by an α6β1-binding-deficient mutant Ccn1-dm, were used in the carotid artery ligation model. In comparison with the wild-type mice, Ccn1dm/dm mice displayed significantly less neointima after ligation, with improved endothelial function and lower oxidative stress, suggesting that the arterial expression of CCN1 induces endothelial dysfunction through binding with integrin α6β1. CCN1 and its receptor integrin α6β1 represent as potential therapeutic targets for atherosclerosis.
論文目次 目錄
摘要 I
英文延伸摘要 II
誌謝 V
目錄 VI
圖目錄 IX
縮寫檢索表 X
第一章 緒論 1
1.1 心血管疾病 (Cardiovascular diseases, CVDs) 1
1.2 動脈粥狀硬化(Atherosclerosis) 1
1.3 動脈粥狀硬化之過程 2
1.4 動脈粥狀硬化之治療 2
1.5 動脈粥狀硬化之動物模式 3
1.6 內皮細胞功能失調 3
1.7 Monocyte Chemoattractant Protein-1(MCP-1,又稱CCL2) 4
1.8 Endothelin-1(ET-1) 5
1.9 von Willebrand Factor(vWF) 6
1.10 CCN家族 6
1.11 CCN1蛋白 7
1.12 CCN1之活性 8
1.13 主要研究目的 8
第二章 材料與方法 10
2.1 化學試劑 / 藥品 10
2.2 其他材料 11
2.3 儀器設備 12
2.4 溶液配方 13
2.5 實驗動物 16
2.6 動物繁殖 16
2.7 基因定型分析(Genotyping) 16
2.8 頸動脈結紮動物模式(Carotid artery ligation model) 18
2.9 組織切片製備 19
2.10 組織切片 19
2.11 H&E染色 20
2.12 組織分析 20
2.13 全標本(Whole mount) X-gal染色 21
2.14 免疫螢光染色 22
2.15 TUNEL染色 24
2.16 資料分析 24
第三章 結果 25
3.1 頸動脈結紮產生擾流進而引起血管重塑(Remodeling) 25
3.2 CCN1受擾流所誘發 25
3.3 CCN1由內皮細胞、平滑肌細胞以及巨噬細胞製造出來 26
3.4 CCN1透過整合素α6β1來調控血管內膜新生 26
3.5 CCN1透過整合素α6β1影響內皮細胞的氧化壓力、損傷、再生修復和功能 27
第四章 討論 29
第五章 結論 33
第六章 參考文獻 34
第七章 附錄 46
7.1 主動脈結構 46
7.2 CCN家族結構 47
7.3 頸動脈結紮模式(Carotid artery ligation model) 48
第八章 圖表 49
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